A detailed understanding of the nnolecular and cellular events influencing the three key dimensions of cellular life (growth/proliferation, survival, and differentiation) remains a central question in cancer biology. Further understanding of the influence of the ubiquitin system on the transformation process will help to identify novel targets for cancer therapy. The first years of work under CA76584 (started in 1998) set the bases for elucidating the role played by F-box proteins in human oncogenesis, which was accomplished during the second funding cycle. In its third cycle, CA76584 is currently devoted to elucidating the integration of the ubiquitin system in the signaling networks of the cell, and its corruption in cancer. In particular, our research program involves the study of the human family of SCF and SCF-like ubiquitin ligases to gain an understanding of the molecular mechanisms through which they control basic cellular processes, such as cell growth, cell division, and cell survival. To this end, we are using a comprehensive and interdisciplinary approach that includes biochemical and biological methods, as well as somatic cell and mouse genetics. These tools, together with our expertise in the ubiquitin system, will ensure that our laboratory will continue to contribute to the understanding of cell functions during the coming years. As the mechanisms of the ubiquitin-mediated proteolysis of cell cycle regulators are unraveled, this team is committed to the integration of its basic research results with an understanding of malignant transformation.